Genetic Variation in Phosphodiesterase (PDE) 7B in Chronic Lymphocytic Leukemia: Overview of Genetic Variants of Cyclic Nucleotide Pdes in Human Disease
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Reprogramming Metabolism by Targeting Sirtuin 6 Attenuates Retinal Degeneration
The Journal of Clinical Investigation RESEARCH ARTICLE Reprogramming metabolism by targeting sirtuin 6 attenuates retinal degeneration Lijuan Zhang,1,2,3 Jianhai Du,4 Sally Justus,1,2 Chun-Wei Hsu,1,2 Luis Bonet-Ponce,5 Wen-Hsuan Wu,1,2 Yi-Ting Tsai,1,2 Wei-Pu Wu,1,2 Yading Jia,2 Jimmy K. Duong,6 Vinit B. Mahajan,7 Chyuan-Sheng Lin,8 Shuang Wang,6 James B. Hurley,4 and Stephen H. Tsang1,2,9 1The Jonas Children’s Vision Care and Bernard & Shirlee Brown Glaucoma Laboratory, Department of Ophthalmology, Columbia University, New York, New York, USA. 2Edward S. Harkness Eye Institute, New York-Presbyterian Hospital, New York, New York, USA. 3Shanxi Eye Hospital, affiliated with Shanxi Medical University, Xinghualing, Taiyuan, China. 4Department of Biochemistry and Ophthalmology, University of Washington, Seattle, Washington, USA. 5Section on Retinal Ganglion Cell Biology, Laboratory of Retinal Cell and Molecular Biology, NIH, Bethesda, Maryland, USA. 6Department of Biostatistics, Mailman School of Public Health, Columbia University Medical Center, New York, New York, USA. 7Omics Lab, University of Iowa, Iowa City, Iowa, USA. 8Department of Pathology and Cell Biology, Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons of Columbia University, New York, New York, USA. 9Departments of Pathology and Cell Biology, Institute of Human Nutrition, College of Physicians and Surgeons, Columbia University, New York, New York, USA. Retinitis pigmentosa (RP) encompasses a diverse group of Mendelian disorders leading to progressive degeneration of rods and then cones. For reasons that remain unclear, diseased RP photoreceptors begin to deteriorate, eventually leading to cell death and, consequently, loss of vision. -
Nucleotide Metabolism
NUCLEOTIDE METABOLISM General Overview • Structure of Nucleotides Pentoses Purines and Pyrimidines Nucleosides Nucleotides • De Novo Purine Nucleotide Synthesis PRPP synthesis 5-Phosphoribosylamine synthesis IMP synthesis Inhibitors of purine synthesis Synthesis of AMP and GMP from IMP Synthesis of NDP and NTP from NMP • Salvage pathways for purines • Degradation of purine nucleotides • Pyrimidine synthesis Carbamoyl phosphate synthesisOrotik asit sentezi • Pirimidin nükleotitlerinin yıkımı • Ribonükleotitlerin deoksiribonükleotitlere dönüşümü Basic functions of nucleotides • They are precursors of DNA and RNA. • They are the sources of activated intermediates in lipid and protein synthesis (UDP-glucose→glycogen, S-adenosylmathionine as methyl donor) • They are structural components of coenzymes (NAD(P)+, FAD, and CoA). • They act as second messengers (cAMP, cGMP). • They play important role in carrying energy (ATP, etc). • They play regulatory roles in various pathways by activating or inhibiting key enzymes. Structures of Nucleotides • Nucleotides are composed of 1) A pentose monosaccharide (ribose or deoxyribose) 2) A nitrogenous base (purine or pyrimidine) 3) One, two or three phosphate groups. Pentoses 1.Ribose 2.Deoxyribose •Deoxyribonucleotides contain deoxyribose, while ribonucleotides contain ribose. •Ribose is produced in the pentose phosphate pathway. Ribonucleotide reductase converts ribonucleoside diphosphate deoxyribonucleotide. Nucleotide structure-Base 1.Purine 2.Pyrimidine •Adenine and guanine, which take part in the structure -
2'-Deoxyguanosine Toxicity for B and Mature T Lymphoid Cell Lines Is Mediated by Guanine Ribonucleotide Accumulation
2'-deoxyguanosine toxicity for B and mature T lymphoid cell lines is mediated by guanine ribonucleotide accumulation. Y Sidi, B S Mitchell J Clin Invest. 1984;74(5):1640-1648. https://doi.org/10.1172/JCI111580. Research Article Inherited deficiency of the enzyme purine nucleoside phosphorylase (PNP) results in selective and severe T lymphocyte depletion which is mediated by its substrate, 2'-deoxyguanosine. This observation provides a rationale for the use of PNP inhibitors as selective T cell immunosuppressive agents. We have studied the relative effects of the PNP inhibitor 8- aminoguanosine on the metabolism and growth of lymphoid cell lines of T and B cell origin. We have found that 2'- deoxyguanosine toxicity for T lymphoblasts is markedly potentiated by 8-aminoguanosine and is mediated by the accumulation of deoxyguanosine triphosphate. In contrast, the growth of T4+ mature T cell lines and B lymphoblast cell lines is inhibited by somewhat higher concentrations of 2'-deoxyguanosine (ID50 20 and 18 microM, respectively) in the presence of 8-aminoguanosine without an increase in deoxyguanosine triphosphate levels. Cytotoxicity correlates instead with a three- to fivefold increase in guanosine triphosphate (GTP) levels after 24 h. Accumulation of GTP and growth inhibition also result from exposure to guanosine, but not to guanine at equimolar concentrations. B lymphoblasts which are deficient in the purine salvage enzyme hypoxanthine guanine phosphoribosyltransferase are completely resistant to 2'-deoxyguanosine or guanosine concentrations up to 800 microM and do not demonstrate an increase in GTP levels. Growth inhibition and GTP accumulation are prevented by hypoxanthine or adenine, but not by 2'-deoxycytidine. -
Impedes Transport of GRK1 and PDE6 Catalytic Subunits to Photoreceptor Outer Segments
Deletion of PrBP/␦ impedes transport of GRK1 and PDE6 catalytic subunits to photoreceptor outer segments H. Zhang*, S. Li*, T. Doan†, F. Rieke†‡, P. B. Detwiler†, J. M. Frederick*, and W. Baehr*§¶ʈ *John A. Moran Eye Center, University of Utah Health Science Center, Salt Lake City, UT 84132; †Department of Physiology and Biophysics and ‡Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195; and Departments of §Neurobiology and Anatomy and ¶Biology, University of Utah, Salt Lake City, UT 84112 Edited by Jeremy Nathans, Johns Hopkins University School of Medicine, Baltimore, MD, and approved April 11, 2007 (received for review February 23, 2007) The mouse Pde6d gene encodes a ubiquitous prenyl binding chains (5, 7). Posttranslational sorting and targeting of proteins protein, termed PrBP/␦, of largely unknown physiological function. occurs in all cells and is of particular importance in photore- PrBP/␦ was originally identified as a putative rod cGMP phospho- ceptors, which renew their entire outer segments roughly every diesterase (PDE6) subunit in the retina, where it is relatively 10 days (8). Because of compartmentalization of inner and outer abundant. To investigate the consequences of Pde6d deletion in segments and very active metabolism, photoreceptors are re- .retina, we generated a Pde6d؊/؊ mouse by targeted recombina- garded as model cells to study protein trafficking tion. Although manifesting reduced body weight, the Pde6d؊/؊ PrBP/␦, originally thought to be a subunit of PDE6 and termed mouse was viable and fertile and its retina developed normally. PDE␦ (9), was shown recently to be a prenyl binding protein (10, Immunocytochemistry showed that farnesylated rhodopsin kinase 11) and subsequently named PrBP/␦ to reflect this fact (12). -
It Takes Two Transducins to Activate the Cgmp-Phosphodiesterase 6 in Retinal Rods Rsob.Royalsocietypublishing.Org Bilal M
It takes two transducins to activate the cGMP-phosphodiesterase 6 in retinal rods rsob.royalsocietypublishing.org Bilal M. Qureshi1,†,‡, Elmar Behrmann1,†,}, Johannes Scho¨neberg2,jj, Justus Loerke1,Jo¨rg Bu¨rger1, Thorsten Mielke1,3, Jan Giesebrecht1,§, Frank Noe´2, Trevor D. Lamb4, Klaus Peter Hofmann1,5, Christian M. T. Spahn1 and Martin Heck1 Research 1Institut fu¨r Medizinische Physik und Biophysik, Charite´ – Universita¨tsmedizin Berlin, corporate member Cite this article: Qureshi BM et al. 2018 It of Freie Universita¨t Berlin, Humboldt-Universita¨t zu Berlin, and Berlin Institute of Health, Berlin, Germany 2Department of Mathematics, Computer Science and Bioinformatics, Freie Universita¨t Berlin, Berlin, Germany takes two transducins to activate the cGMP- 3Microscopy and Cryo Electron Microscopy Group, Max-Planck Institut fu¨r Molekulare Genetik, Berlin, Germany phosphodiesterase 6 in retinal rods. Open Biol. 4Eccles Institute of Neuroscience, John Curtin School of Medical Research, Australian National University, 8: 180075. Canberra, Australian Capital Territory 2600, Australia 5 http://dx.doi.org/10.1098/rsob.180075 Zentrum fu¨r Biophysik und Bioinformatik, Humboldt-Universita¨t zu Berlin, Berlin, Germany BMQ, 0000-0002-0153-7729; TDL, 0000-0003-0299-6115; MH, 0000-0003-0847-5038 Received: 28 April 2018 Accepted: 6 July 2018 Among cyclic nucleotide phosphodiesterases (PDEs), PDE6 is unique in serving as an effector enzyme in G protein-coupled signal transduction. In Subject Area: retinal rods and cones, PDE6 is membrane-bound and activated to hydrolyse biochemistry/biophysics/structural biology its substrate, cGMP, by binding of two active G protein a-subunits (Ga*). To investigate the activation mechanism of mammalian rod PDE6, we Keywords: have collected functional and structural data, and analysed them by reac- PDE6, visual signal transduction, coincidence tion–diffusion simulations. -
G Protein-Coupled Receptors
www.aladdin-e.com Address:800 S Wineville Avenue, Ontario, CA 91761,USA Website:www.aladdin-e.com Email USA: [email protected] Email EU: [email protected] Email Asia Pacific: [email protected] G PROTEIN-COUPLED RECEPTORS Overview: The completion of the Human Genome Project allowed the identification of a large family of proteins with a common motif of seven groups of 20–24 hydrophobic amino acids arranged as a-helices. Approximately 800 of these seven transmembrane (7TM) receptors have been identified of which over 300 are non-olfactory receptors (see Fredriksson et al., 2003; Lagerstrom and Schioth, 2008). Subdivision on the basis of sequence homology allows the definition of rhodopsin, secretin, adhesion, glutamate and Frizzled receptor families. NC-IUPHAR recognizes Classes A, B, and C, which equate to the rhodopsin, secretin, and glutamate receptor families. The nomenclature of 7TM receptors is commonly used interchangeably with G protein-coupled receptors (GPCR), although the former nomenclature recognises signalling of 7TM receptors through pathways not involving G proteins. For example, adiponectin and membrane progestin receptors have some sequence homology to 7TM receptors but signal independently of G proteins and appear to reside in membranes in an inverted fashion compared to conventional GPCR. Additionally, the NPR-C natriuretic peptide receptor (see Page S195) has a single transmembrane domain structure, but appears to couple to G proteins to generate cellular responses. The 300+ non-olfactory GPCR are the targets for the majority of drugs in clinical usage (Overington et al., 2006), although only a minority of these receptors are exploited therapeutically. -
Nucleotide Metabolism 22
Nucleotide Metabolism 22 For additional ancillary materials related to this chapter, please visit thePoint. I. OVERVIEW Ribonucleoside and deoxyribonucleoside phosphates (nucleotides) are essential for all cells. Without them, neither ribonucleic acid (RNA) nor deoxyribonucleic acid (DNA) can be produced, and, therefore, proteins cannot be synthesized or cells proliferate. Nucleotides also serve as carriers of activated intermediates in the synthesis of some carbohydrates, lipids, and conjugated proteins (for example, uridine diphosphate [UDP]-glucose and cytidine diphosphate [CDP]- choline) and are structural components of several essential coenzymes, such as coenzyme A, flavin adenine dinucleotide (FAD[H2]), nicotinamide adenine dinucleotide (NAD[H]), and nicotinamide adenine dinucleotide phosphate (NADP[H]). Nucleotides, such as cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), serve as second messengers in signal transduction pathways. In addition, nucleotides play an important role as energy sources in the cell. Finally, nucleotides are important regulatory compounds for many of the pathways of intermediary metabolism, inhibiting or activating key enzymes. The purine and pyrimidine bases found in nucleotides can be synthesized de novo or can be obtained through salvage pathways that allow the reuse of the preformed bases resulting from normal cell turnover. [Note: Little of the purines and pyrimidines supplied by diet is utilized and is degraded instead.] II. STRUCTURE Nucleotides are composed of a nitrogenous base; a pentose monosaccharide; and one, two, or three phosphate groups. The nitrogen-containing bases belong to two families of compounds: the purines and the pyrimidines. A. Purine and pyrimidine bases Both DNA and RNA contain the same purine bases: adenine (A) and guanine (G). -
G Protein-Coupled Receptors
G PROTEIN-COUPLED RECEPTORS Overview:- The completion of the Human Genome Project allowed the identification of a large family of proteins with a common motif of seven groups of 20-24 hydrophobic amino acids arranged as α-helices. Approximately 800 of these seven transmembrane (7TM) receptors have been identified of which over 300 are non-olfactory receptors (see Frederikson et al., 2003; Lagerstrom and Schioth, 2008). Subdivision on the basis of sequence homology allows the definition of rhodopsin, secretin, adhesion, glutamate and Frizzled receptor families. NC-IUPHAR recognizes Classes A, B, and C, which equate to the rhodopsin, secretin, and glutamate receptor families. The nomenclature of 7TM receptors is commonly used interchangeably with G protein-coupled receptors (GPCR), although the former nomenclature recognises signalling of 7TM receptors through pathways not involving G proteins. For example, adiponectin and membrane progestin receptors have some sequence homology to 7TM receptors but signal independently of G-proteins and appear to reside in membranes in an inverted fashion compared to conventional GPCR. Additionally, the NPR-C natriuretic peptide receptor has a single transmembrane domain structure, but appears to couple to G proteins to generate cellular responses. The 300+ non-olfactory GPCR are the targets for the majority of drugs in clinical usage (Overington et al., 2006), although only a minority of these receptors are exploited therapeutically. Signalling through GPCR is enacted by the activation of heterotrimeric GTP-binding proteins (G proteins), made up of α, β and γ subunits, where the α and βγ subunits are responsible for signalling. The α subunit (tabulated below) allows definition of one series of signalling cascades and allows grouping of GPCRs to suggest common cellular, tissue and behavioural responses. -
De Novo Deoxyribonucleotide Biosynthesis Regulates Cell Growth
www.nature.com/scientificreports OPEN De novo deoxyribonucleotide biosynthesis regulates cell growth and tumor progression in small‑cell lung carcinoma Ami Maruyama1,2,3, Yuzo Sato1,2,4,5, Joji Nakayama1,2,3, Junko Murai4,5, Takamasa Ishikawa5,6, Tomoyoshi Soga4,5 & Hideki Makinoshima1,2,3,7* Deoxyribonucleotide biosynthesis from ribonucleotides supports the growth of active cancer cells by producing building blocks for DNA. Although ribonucleotide reductase (RNR) is known to catalyze the rate‑limiting step of de novo deoxyribonucleotide triphosphate (dNTP) synthesis, the biological function of the RNR large subunit (RRM1) in small‑cell lung carcinoma (SCLC) remains unclear. In this study, we established siRNA‑transfected SCLC cell lines to investigate the anticancer efect of silencing RRM1 gene expression. We found that RRM1 is required for the full growth of SCLC cells both in vitro and in vivo. In particular, the deletion of RRM1 induced a DNA damage response in SCLC cells and decreased the number of cells with S phase cell cycle arrest. We also elucidated the overall changes in the metabolic profle of SCLC cells caused by RRM1 deletion. Together, our fndings reveal a relationship between the deoxyribonucleotide biosynthesis axis and key metabolic changes in SCLC, which may indicate a possible link between tumor growth and the regulation of deoxyribonucleotide metabolism in SCLC. Small-cell lung carcinoma (SCLC) is a neuroendocrine tumor subtype of lung cancer, and it is associated with a poor prognosis1–3. In particular, SCLC is characterized by early and widespread metastatic dissemination and a remarkable response to chemotherapy that is almost invariably followed by the development of drug resistance4. -
PDE6) by the Glutamic Acid- Rich Protein-2 (GARP2)
University of New Hampshire University of New Hampshire Scholars' Repository Doctoral Dissertations Student Scholarship Fall 2013 Regulation of the catalytic and allosteric properties of photoreceptor phosphodiesterase (PDE6) by the glutamic acid- rich protein-2 (GARP2) Wei Yao Follow this and additional works at: https://scholars.unh.edu/dissertation Recommended Citation Yao, Wei, "Regulation of the catalytic and allosteric properties of photoreceptor phosphodiesterase (PDE6) by the glutamic acid-rich protein-2 (GARP2)" (2013). Doctoral Dissertations. 747. https://scholars.unh.edu/dissertation/747 This Dissertation is brought to you for free and open access by the Student Scholarship at University of New Hampshire Scholars' Repository. It has been accepted for inclusion in Doctoral Dissertations by an authorized administrator of University of New Hampshire Scholars' Repository. For more information, please contact [email protected]. REGULATION OF THE CATALYTIC AND ALLOSTERIC PROPERTIES OF PHOTORECEPTOR PHOSPHODIESTERASE (PDE6) BY THE GLUTAMIC ACID-RICH PROTEIN-2 (GARP2) BY WEI YAO B.S., Jinan University, 2007 DISSERTATION Submitted to the University of New Hampshire in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy in Biochemistry September, 2013 UMI Number: 3575987 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. Di!ss0?t&iori Piiblist’Mlg UMI 3575987 Published by ProQuest LLC 2013. Copyright in the Dissertation held by the Author. -
Balancing the Photoreceptor Proteome: Proteostasis Network Therapeutics for Inherited Retinal Disease
G C A T T A C G G C A T genes Review Balancing the Photoreceptor Proteome: Proteostasis Network Therapeutics for Inherited Retinal Disease Siebren Faber and Ronald Roepman * Department of Human Genetics and Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GA Nijmegen, The Netherlands * Correspondence: [email protected] Received: 10 June 2019; Accepted: 16 July 2019; Published: 24 July 2019 Abstract: The light sensing outer segments of photoreceptors (PRs) are renewed every ten days due to their high photoactivity, especially of the cones during daytime vision. This demands a tremendous amount of energy, as well as a high turnover of their main biosynthetic compounds, membranes, and proteins. Therefore, a refined proteostasis network (PN), regulating the protein balance, is crucial for PR viability. In many inherited retinal diseases (IRDs) this balance is disrupted leading to protein accumulation in the inner segment and eventually the death of PRs. Various studies have been focusing on therapeutically targeting the different branches of the PR PN to restore the protein balance and ultimately to treat inherited blindness. This review first describes the different branches of the PN in detail. Subsequently, insights are provided on how therapeutic compounds directed against the different PN branches might slow down or even arrest the appalling, progressive blinding conditions. These insights are supported by findings of PN modulators in other research disciplines. Keywords: protein trafficking; protein folding; protein degradation; chaperones; chaperonins; heat shock response; unfolded protein response; autophagy; therapy 1. Introduction The rod and cone photoreceptor (PR) cells are the most abundant cell types in the human retina, with ~6.4 million cones and up to 125 million rods per adult retina [1]. -
Phosphodiesterase Inhibitors: Their Role and Implications
International Journal of PharmTech Research CODEN (USA): IJPRIF ISSN : 0974-4304 Vol.1, No.4, pp 1148-1160, Oct-Dec 2009 PHOSPHODIESTERASE INHIBITORS: THEIR ROLE AND IMPLICATIONS Rumi Ghosh*1, Onkar Sawant 1, Priya Ganpathy1, Shweta Pitre1 and V.J.Kadam1 1Dept. of Pharmacology ,Bharati Vidyapeeth’s College of Pharmacy, University of Mumbai, Sector 8, CBD Belapur, Navi Mumbai -400614, India. *Corres.author: rumi 1968@ hotmail.com ABSTRACT: Phosphodiesterase (PDE) isoenzymes catalyze the inactivation of intracellular mediators of signal transduction such as cAMP and cGMP and thus have pivotal roles in cellular functions. PDE inhibitors such as theophylline have been employed as anti-asthmatics since decades and numerous novel selective PDE inhibitors are currently being investigated for the treatment of diseases such as Alzheimer’s disease, erectile dysfunction and many others. This review attempts to elucidate the pharmacology, applications and recent developments in research on PDE inhibitors as pharmacological agents. Keywords: Phosphodiesterases, Phosphodiesterase inhibitors. INTRODUCTION Alzheimer’s disease, COPD and other aliments. By cAMP and cGMP are intracellular second messengers inhibiting specifically the up-regulated PDE isozyme(s) involved in the transduction of various physiologic with newly synthesized potent and isoezyme selective stimuli and regulation of multiple physiological PDE inhibitors, it may possible to restore normal processes, including vascular resistance, cardiac output, intracellular signaling selectively, providing therapy with visceral motility, immune response (1), inflammation (2), reduced adverse effects (9). neuroplasticity, vision (3), and reproduction (4). Intracellular levels of these cyclic nucleotide second AN OVERVIEW OF THE PHOSPHODIESTERASE messengers are regulated predominantly by the complex SUPER FAMILY superfamily of cyclic nucleotide phosphodiesterase The PDE super family is large, complex and represents (PDE) enzymes.